Piperidine opioid antagonists

ABSTRACT

This invention provides trans-3,4 1-substituted-3-substituted-4-methyl-4-(3-substituted phenyl)piperidines as opioid antagonists capable of blocking the mu or kappa receptors in the brain.

This application is a division, of application Ser. No. 07/284,504,filed 12/14/88, now U.S. Pat. No. 4,891,379, which is a continuation ofSer. No. 07/039,121, filed Apr. 16, 1987, now abandoned.

SUMMARY OF THE INVENTION

The present invention relates to a trans-3,4 isomer of a compound of theformula ##STR1## wherein: R¹ is hydrogen or C₁ -C₄ alkanoyl;

R² is hydrogen, C₁ -C₄ alkyl or C₂ -C₆ alkenyl;

R³ is C₄ -C₈ cycloalkyl, C₄ -C₈ cycloalkenyl, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₁ -C₄ alkyl substituted C₄ -C₈ cycloalkyl, C₁ -C₄ alkylsubstituted C₄ -C₈ cycloalkenyl or thiophene;

Z is ##STR2## or a bond; R⁴ is hydrogen, C₁ -C₆ alkyl, ##STR3## or##STR4## R⁵ is C₁ -C₄ alkyl or ##STR5## n is 1, 2 or 3; and thepharmaceutically acceptable salts thereof.

The present invention also provides methods of employing, andpharmaceutical formulations containing, a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The term "C₁ -C₄ alkanoyl", as used herein, represents an alkanonylgroup having from one to four carbon atoms. Typical C₁ -C₄ alkanoylgroups include acyl, propanoyl, butanoyl and the like.

C₄ -C₈ Cycloalkyl represents cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

C₄ -C₈ Cycloalkenyl includes cyclobutenyl, cyclopentyl, cyclohexenyl,cycloheptenyl, cyclooctenyl and the like.

C₁ -C₆ Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and the like.

C₂ -C₆ Alkenyl includes vinyl, allyl, 3-butenyl,3-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like.

C₁ -C₄ Alkyl substituted C₄ -C₈ cycloalkyl represents a C₄ -C₈cycloalkyl group having one or more C₁ -C₄ alkyl substituents. TypicalC₁ -C₄ alkyl substituted C₄ -C₈ cycloalkyl groups includecyclobutylmethyl, 2-cyclobutylpropyl,(2-methylcyclobutyl)methyl,2-cyclohexylethyl, and the like.

C₁ -C₄ Alkyl substituted C₄ -C₈ cycloalkenyl represents a C₄ -C₈cycloalkenyl group having one or more C₁ -C₄ alkyl groups. Typical C₁-C₄ alkyl substituted C₄ -C₈ cycloalkenyl groups includecyclobutenylmethyl, cyclopropenylethyl, (2-ethylcyclohexenyl)methyl, andthe like.

C₁ -C₆ Alkoxy represents a straight or branched alkoxy chain having fromone to six carbon atoms. Typical C₁ -C₆ alkoxy groups are methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, n-propoxy and the like.

"Halo" or "halogen" represents fluoro, chloro, bromo or iodo.

Thiophene means 2-thiophene or 3-thiophene.

While all of the compounds of the present invention are useful opioidantagonists, certain of the present compounds are preferred for thatuse. Preferably, Z is ##STR6## R¹ R² and R⁴ are hydrogen, and R³ is C₄-C₈ cycloalkyl, and especially cyclohexyl. Also, the compoundspreferably exist as pharmaceutically acceptable salts. Other preferredaspects of the present invention will be noted hereinafter.

The piperidines of the invention as illustrated in formula I occur asthe trans stereochemical isomers by virtue of the substituents at the 3-and 4-positions. More specifically, the alkyl or alkenyl group at the3-position is situated in a trans position relative to the methyl groupat the 4-position. As such, the compounds can exist as the trans (+)isomer of the formula ##STR7## or the trans (-) isomer of the formula##STR8## The present invention comtemplates both the individual trans(+) and (-) stereoisomers, as well as the racemic mixture of the transstereoisomers.

Also, when Z is ##STR9## the carbon atom attached to the OR⁴ group isasymmetric. As such, this class of compounds can further exist as theindividual R or S stereoisomers, or the racemic mixture of the isomers,and all are contemplated within the scope of the compounds of thepresent invention.

The piperidines of this invention form pharmaceutically acceptable acidaddition salts with a wide variety of inorganic and organic acids. Theparticular acid used in salt formation is not critical; however, thecorresponding salt that is formed must be substantially non-toxic toanimals. Typical acids generally used include sulfuric, hydrochloric,hydrobromic, phosphoric, hydroiodic, sulfamic, citric, acetic, maleic,malic, succinic, tartaric, cinnamic, benzoic, ascorbic, and relatedacids. The piperidines additionally form quaternary ammonium salts witha variety of organic esters of sulfuric, hydrohalic and aromaticsulfonic acids, and the like. Among such esters are methyl chloride,ethyl bromide, propyl iodide, butyl bromide, allyl iodide, isobutylchloride, benzyl bromide, dimethyl sulfate, diethyl sulfate, methylbenzensulfonate, ethyl toluenesulfonate, crotyl iodide, and the like.

The compounds of the present invention may be prepared by a variety ofprocedures well known to those of ordinary skill in the art. Thepreferred procedure involves the reaction of a3-substituted-4-methyl-4-(3-substituted phenyl)piperidine with anappropriate acylating agent to provide the corresponding intermediate,which is reduced to the compound of the present invention under standardconditions. This reaction may be represented by the following scheme:##STR10## wherein R¹, R², R³ and Z are as defined above and X is --OH,or a good leaving group such as ##STR11## C₁ -C₆ alkoxy or halogen.

The first step of the above-described process wherein X is hydroxynecessitates the use coupling reagents commonly employed in thesynthesis of peptides. Examples of such coupling reagents include thecarbodiimides such as N,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide, or N,N'-diethylcarbodiimide; theimidazoles such as carbonyldiimidazole; as well as reagents such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The directcoupling of a substituted carboxylic acid and a3-substituted-4-methyl-4-(3-substitutedphenyl)piperidine is carried outby adding about an equimolar quantity of the piperidine startingmaterial to a solution of the carboxylic acid in the presence of anequimolar quantity or slight excess of coupling reagent. The reactiongenerally is carried out in an unreactive organic solvent such asdichloromethane or N,N-dimethylformamide, and usually is complete withinabout twenty-four hours when conducted at a temperature of about 0° C.to about 30° C. The product is then typically isolated by filtration.The acylated product thus formed can be further purified, if needed, byany of several routine methods, including crystallization from commonsolvents, chromatography over solid supports such as silica or alumina,and related purification techniques.

The reaction wherein X is other than hydroxy is conducted as follows.The preferred leaving group in this reaction is where X is halogen,especially chloro. The reaction can be carried out by combining thesubstituted carboxylic acid derivative with about an equimolar quantityof the 3-substituted-4-methyl-4-(3-substituted phenyl)piperidine in amutual solvent such tetrahydrofuran, diethyl ether, dichloromethane,dioxane, dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene, andthe like. If desired, a base can be utilized in the acylation reactionwhen X is halogen to act as an acid scavenger. Commonly used basesinclude sodium carbonate, potassium carbonate, pyridine, triethylamineand related bases. Bases such as pyridine act as their own solvent andneed no additional solvent. The reaction generally is substantiallycomplete after about two to about 200 hours when carried out at atemperature of about 20° C. to about 200° C., preferably from about 30°C. to about 100° C. The product of the reaction may be isolated bysimply removing the reaction solvent, for instance by evaporation underreduced pressure. Also, the reaction mixture may be added to water, andthe product collected by filtration or extracted into a water immisciblesolvent. The product thus isolated can be further purified, if desired,by any of several well known techniques.

The acylated intermediates thus prepared are finally reduced accordingto standard procedures to provide the present compounds. Typicalreducing agents suitable for use include the hydride reducing agentssuch as lithium aluminum hydride and sodium bis(2-methoxyethoxy)aluminumhydride, which is preferred. Typically, an excess of reducing agent iscombined with the acylated intermediate in a mutual solvent. Thereaction is substantially complete after about one to about 12 hourswhen conducted at a temperature in the range of about 20° C. to about100° C. The desired product may then be isolated by procedures wellknown to those of ordinary skill in the art.

The compounds of the present invention may also be prepared by thedirect substitution of a halogen substituted compound with the3-substituted-4-methyl-4-(3-substituted phenyl)piperidine intermediate.This reaction is represented by the following scheme: ##STR12## whereinR¹, R², R³ and Z are as defined above and Y is halogen.

This reaction is conducted by combining approximately equimolar amountsof the two starting materials in a mutual solvent. A slight excess ofthe halogen substituted compound may be employed to ensure completereaction. Typical mutual solvents suitable for use in this reactioninclude aprotic solvents such as N,N-dimethylformamide and the like.Further, the reaction is preferably conducted in the presence of a base,such as sodium bicarbonate, which acts as an acid scavenger for thehydrohalic acid which is formed as a by-product of the reaction. Thereaction is generally complete after about 30 minutes to 24 hours whenconducted at a temperature in the range of about 40° C. to about 100° C.The product is isolated and purified, if needed, by standard procedures.When R³ is an alkene group in the above reaction, the double bond can besubsequently reduced under standard conditions to provide an alkylsubstituent.

Compounds of the invention wherein Z is ##STR13## may be prepared by thereaction of the 3-substituted-4-methyl-4-(3-substitutedphenyl)piperidine starting material with an appropriately substitutedketo substituted alkene. This reaction is represented by the followingscheme: ##STR14## wherein R¹, R² and R³ are as defined above.

This reaction is conducted by combining approximately equimolarquantities of the starting materials in a mutual solvent such asN,N-dimethylformamide. The reaction is substantially complete afterabout 10 minutes to about 24 hours when conducted at a temperature inthe range of about 20° C. to about 150° C. The product is isolated bystandard procedures and purified, if desired, to provide a compound ofthe invention.

Compounds of the invention wherein Z is ##STR15## and R⁴ is hydrogen arepreferably prepared by reducing the corresponding compound wherein Z is##STR16## with a standard reducing agent such as any of the hydridereducing agents, for example lithium aluminum hydride, sodiumborohydride and the like. This reaction is conducted in a non-reactivesolvent, with any residual water preferable removed, such astetrahydrofuran, diethyl ether, and related solvents. The product isisolated by standard procedures. When R⁴ is C₁ -C₆ alkyl or benzyl,phenethyl, or phenpropyl, the alkali metal anion is formed with the R⁴=hydrogen compound, and reacted with the corresponding halidederivative. When R⁴ is acyl, the R⁴ =hydrogen compound is acylated withan acyl halide, for example, according to standard acylation conditions.

Salts of piperidines are prepared by methods commonly employed for thepreparation of amine salts. In particular, acid addition salts of thepiperidines are prepared by reaction of the piperidine with anappropriate acid of pKa less than about 4, generally in an unreactiveorganic solvent. Suitable acids include mineral acids such ashydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, and likeacids. Organic acids are also used, for example acetic acid,p-toluenesulfonic acid, chloroacetic acid, and the like. The usualsolvents used in the reaction include acetone, tetrahydrofuran, diethylether, ethyl acetate, and the like. Quaternary salts can be prepared ingenerally the same way by reaction of the piperidine with analkylsulfate or alkyl halide, for example, methyl sulfate, methyliodide, ethyl bromide, propyl iodide, and the like.

The 3-substituted-4-methyl-4-(3-hydroxy- or-alkanoyloxyphenyl)piperidine derivatives employed as starting materialsin the synthesis of the compounds of the present invention are preparedby the general procedure taught by Zimmerman in U.S. Pat. No. 4,081,450,herein incorporated by reference. The compounds wherein R² is hydrogenare preferably prepared by the procedure of Barnett in U.S. Pat. No.4,581,456, herein incorporated by reference, but adjusted so thatβ-stereochemistry is preferred, in contrast to the α-stereochemistrywhich is preferred by the process taught in the Barnett patent.According to the Barnett procedure, a 3-alkoxybromobenzene derivative isconverted to the 3-alkoxyphenyllithium analog by reaction with analkyllithium reagent. The 3-alkoxyphenyllithium derivative is reactedwith a 1-alkyl-4-piperidone to provide the corresponding1-alkyl-4-(3-alkoxyphenyl)piperidinol derivative. The piperidinol thusprepared is dehydrated with acid to provide the corresponding1-alkyl-4-(3-alkoxyphenyl)tetrahydropyridine derivative, which readilyundergoes a metalloenamine alkylation to provide the appropriate1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine derivative. Thecompound thus prepared is converted to a 1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamine uponreaction with formaldehyde, an appropriate amine and sulfuric acid.Next, the methanamine is catalytically hydrogenated to the1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)piperidine, which is finallydealkylated at the 1-position, and the methoxy group is converted to ahydroxy group at the 3-position of the phenyl ring to provide the3,4-dimethyl-4-(3-hydroxyphenyl)piperidine starting material employed inthe present invention. This reaction sequence will be readily understoodby the following scheme: ##STR17## wherein R⁶ is C₁ -C₃ alkoxy, R⁷ is C₁-C₆ alkyl, R⁸ is C₁ -C₄ alkyl, R⁹ and R¹⁰ independently are C₁ -C₃ alkylor, when taken together with the nitrogen atom to which they areattached, form piperidine, piperazine, N-methylpiperazine, morpholine orpyrrolidine, and Y is halogen.

The first step of the above-described process involves the formation ofthe 3-alkoxyphenyllithium reagent by reacting 3-alkoxybromobenzene withan alkyllithium reagent. This reaction is typically performed underinert conditions and in the presence of a suitable non-reactive solventsuch as dry diethyl ether or preferably dry tetrahydrofuran. Preferredalkyllithium reagents used in this process are n-butyllithium, andespecially sec.-butyllithium. Generally, approximately an equimolar toslight excess of alkyllithium reagent is added to the reaction mixture.The reaction is conducted at a temperature between about -20° C. andabout -100° C., more preferably from about -50° C. to about -55° C.

Once the 3-alkoxyphenyllithium reagent has formed, approximately anequimolar quantity of a 1-alkyl-4-piperidone is added to the mixturewhile maintaining the temperature between -20° C. and -100° C. Thereaction is typically complete after about 1 to 24 hours. At this point,the reaction mixture is allowed to gradually warm to room temperature.The product is isolated by the addition to the reaction mixture of asaturated sodium chloride solution in order to quench any residuallithium reagent. The organic layer is separated and further purified ifdesired to provide the appropriate 1-alkyl-4-(3-alkoxyphenyl)piperidinolderivative.

The dehydration of the 4-phenylpiperidinol prepared above isaccomplished with a strong acid according to well known procedures.While dehydration occurs in various amounts with any one of severalstrong acids such as hydrochloric acid, hydrobromic acid, and the like,dehydration is preferably conducted with phosphoric acid, or especiallyp-toluenesulfonic acid and toluene or benzene. This reaction istypically conducted under reflux conditions, more generally from about50° C. to about 150° C. The product thus formed is generally isolated bybasifying an acidic aqueous solution of the salt form of the product andextracting the aqueous solution with any one of several water immisciblesolvents. The resulting residue following evaporation may then befurther purified if desired.

The 1-alkyl-4-methyl-4-(3-alkoxyphenyl)-tetrahydropyridine derivativesare prepared by a metalloenamine alkylation. This reaction is preferablyconducted with n-butyllithium in tetrahydrofuran under an inertatmosphere, such as nitrogen or argon. Generally, a slight excess ofn-butyllithium is added to a stirring solution of the1-alkyl-4-(3-alkoxyphenyl)-tetrahydropyridine in THF cooled to atemperature in the range of from about -50° C. to about 0° C., morepreferably from about -20° C. to about -10° C. This mixture is stirredfor approximately 10 to 30 minutes followed by the addition ofapproximately from 1.0 to 1.5 equivalents of methyl halide to thesolution while maintaining the temperature of the reaction mixture below0° C. After about 5 to 60 minutes, water is added to the reactionmixture and the organic phase is collected. The product may be purifiedaccording to standard procedures, but it is desirable to purify thecrude product by either distilling it under vacuum or slurrying it in amixture of hexane:ethyl acetate (65:35, v:v) and silica gel for abouttwo hours. According to the latter procedure, the product is thenisolated by filtration and evaporating the filtrate under reducedpressure.

The next step in the process involves the application of the Mannichreaction of aminomethylation to non-conjugated, endocyclic enamines.This reaction is carried out by combining from about 1.2 to 2.0equivalents of aqueous formaldehyde and about 1.3 to 2.0 equivalents ofthe secondary amine NHR⁹ R¹⁰ in a suitable solvent. While water is thepreferred solvent, other non-nucleophilic solvents such as acetone andacetonitrile may also be employed in this reaction. The pH of thissolution is adjusted to approximately 3.0-4.0 with an acid whichprovides a non-nucleophilic anion. Examples of such acids includesulfuric acid, the sulfonic acids such as methanesulfonic acid andp-toluenesulfonic acid, phosphoric acid, and tetrafluoroboric acid. Thepreferred acid is sulfuric acid. To this solution is added oneequivalent of a 1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine,typically dissolved in aqueous sulfuric acid, and the pH of the solutionreadjusted to from 3.0-3.5 with the non-nucleophilic acid or a secondaryamine as defined above. While maintenance of this pH during the reactionis preferred for optimum results, this reaction may be conducted at a pHin the range of from about 1.0 to 5.0. The reaction is substantiallycomplete after about 1 to 4 hours, more typically about 2 hours, whenconducted at a temperature in the range of from about 50° C. to about80° C., more preferably at about 70° C. The reaction is next cooled toapproximately 30° C. and added to a sodium hydroxide solution. Thissolution is extracted with a water immiscible organic solvent, such ashexane or ethyl acetate, and the organic phase, following thoroughwashing with water to remove any residual formaldehyde, is evaporated todryness under reduced pressure.

The next step of the process involves the catalytic hydrogenation of the1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamineprepared above to the corresponding trans1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)piperidine. This reactionactually occurs in two steps. The first step is the hydrogenolysisreaction wherein the exo C-N bond is reductively cleaved therebygenerating the 3-methyltetrahydropyridine. In the second step, the2,3-double bond in the tetrahydropyridine ring is reduced therebyaffording the desired piperidine ring.

Reduction of the enamine double bond introduced the crucial relativestereochemistry at the 3 and 4 carbon atoms of the piperidine ring. Thereduction does not occur with complete stereoselectivity. The catalystsemployed in the process are chosen from among the various palladium andpreferably platinum catalysts.

The catalytic hydrogenation step of the process is preferably conductedin an acidic reaction medium. Suitable solvents for use in the processinclude the alcohols, such as methanol or ethanol, as well as ethylacetate, tetrahydrofuran, toluene, hexane, and the like.

Proper stereochemical outcome has been shown to be dependent on thequantity of catalyst employed. The quantity of catalyst required toproduce the desired stereochemical result is dependent upon the purityof the starting materials in regard to the presence or absence ofvarious catalyst poisons.

The hydrogen pressure in the reaction vessel is not critical but may bein the range of from about 5 to 200 psi. Concentration of the startingmaterial by volume should preferably be around 20 ml. of liquid per gramof starting material, although an increased or decreased concentrationof the starting material could also be employed. Under the conditionsspecified herein, the length of time for the catalytic hydrogenation isnot critical because of the inability for over-reduction of themolecule. While the reaction may continue for up to 24 hours or longer,it is not necessary to continue the reduction conditions after theuptake of the theoretical two moles of hydrogen. The product is isolatedby filtering the reaction mixture through infusorial earth andevaporating the filtrate to dryness under reduced pressure. Furtherpurification of the product thus isolated is not necessary andpreferably the diastereomeric mixture is carried directly on to thefollowing reaction.

The alkyl substituent is next removed from the 1-position of thepiperidine ring by standard dealkylation procedures. Preferably, achloroformate derivative, especially the vinyl or phenyl derivatives,are employed and removed with acid. Next, the alkoxy compound preparedabove is demethylated to the corresponding phenol. This reaction isgenerally carried out by reacting the compound in a 48% aqueoushydrobromic acid solution. This reaction is substantially complete afterabout 30 minutes to 24 hours when conducted at a temperature between 50°C. to about 150° C., more preferably at the reflux temperature of thereaction mixture. The mixture is then worked up by cooling the solution,followed by neutralization with base to an approximate pH of 8. Thisaqueous solution is extracted with a water immiscible organic solvent.The residue following evaporation of the organic phase is thenpreferably used directly in the following step.

The compounds employed as starting materials to the compounds of theinvention may also be prepared by brominating the1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamineprepared above at the 3-position, lithiating the bromo intermediate thusprepared, and reacting the bromo intermediate with the halide R² CH₂ Yto provide the corresponding1-alkyl-3-substituted-4-methyl-4-(4-alkoxyphenyl)tetrahydropyridinemethanamine.This compound is then reduced and converted to the starting material asindicated above.

As noted above, the compounds of the present invention may exist as theresolved stereoisomers. The preferred procedure employed to prepare theresolved starting materials used in the synthesis of these compoundsincludes treating a 1,3-dialkyl-4-methyl-4-(3-alkoxyphenyl)piperidinewith either (+)- or (-)-dibenzoyl tartaric acid to provide the resolvedintermediate. This compound is dealkylated at the 1-position with vinylchloroformate and finally converted to the desired4-(3-hydroxyphenyl)piperidine isomer. This reaction is set forth in thefollowing scheme: ##STR18## wherein R², R⁶ and R⁸ are as defined above.

As will be understood by those skilled in the art, the individual transstereoisomers of the invention may also be isolated with either (+)- or(-)-dibenzoyl tartaric, as desired, from the corresponding racemicmixture of the trans isomer compounds of the invention.

The following Examples further illustrate certain of the compounds ofthe present invention, and methods for their preparation. The Examplesare not intended to be limiting to the scope of the invention in anyrespect, and should not be so construed.

EXAMPLE 1trans-(+)-1-(n-Hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

A. trans-(+)-1-(n-Hexanoyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine

A 250 ml round bottom flask was charged with 2.0 g (9.76 mmol) oftrans-(+)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, 100 ml ofN,N-dimethylformamide and 2.90 g (4 ml, 28.8 mmol) of triethylamine. Tothe mixture was added 3.94 g (29.63 mmol) of hexanoyl chloride. Thereaction mixture was refluxed for approximately two hours and cooled toroom temperature. The mixture was poured into 400 ml of water andextracted with diethyl ether three times. The ether extracts werecombined and washed with 1N hydrochloric acid and a saturated sodiumchloride solution. The organic phase was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under vacuum and theresulting residue containingtrans-(+)-1-(n-hexanoyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine wasused directly in the following reaction.

B. A 250 ml round bottom flask was charged with 10 ml of Red-Al (sodiumbis(2-methoxyethoxy)-aluminum hydride from Aldrich Chemical Company,Milwaukee, Wis.) and 20 ml of toluene. To the mixture was added dropwisea solution of the residue isolated above dissolved in approximately 50ml of toluene. The reaction was stirred for approximately 60 minutes atroom temperature and quenched by the addition of 400 ml of a pH 10buffer. The pH of the mixture was adjusted to approximately 9.8 with 1Nhydrochloric acid and the mixture was extracted with toluene. Theorganic extracts were combined and dried over anhydrous sodium sulfate.The filtrate was concentrated under vacuum and the resulting residue waschromatographed over silica gel while eluding with hexane:ethyl acetate(1.5:1, v:v). Fractions containing the major component were combined andthe solvent was evaporated therefrom to provide the desired compound asthe free base. The base was dissolved in diethyl ether and combined withhydrochloric acid to providetrans-(+)-1-(n-hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride.

Analysis calculated for C₁₉ H₃₁ ClNO Theory: C, 70.02; H, 9.90; N, 4.30;Found: C, 70.27; H, 9.99; N, 4.48.

H--NMR (CDCl₃): δ7.30-6.62 (m, 4H); 2.91-1.40 (m, 11H); 1.32 (s, 6H);1.29 (s, 3H); 0.88 (m, 3H); 0.76 (d, 3H, J═7 Hz)

Examples 2-7 were perpared by the general procedure set forth in Example1.

EXAMPLE 2trans-(-)-1-(n-Hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₁ ClNO Theory: C, 70.02; H, 9.90; N, 4.30;Found: C, 70.09; H, 9.81; N, 4.42.

H--NMR (CDCl₃): δ7.30-6.62 (m, 4H); 2.91-1.40 (m, 11H); 1.32 (s, 6H);1.29 (s, 3H); 0.88 (m, 3H); 0.76 (d, 3H, J═7 Hz)

EXAMPLE 3trans-(±)-1-(4-Methyl-4-pentenyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=95°-105° C.

Analysis calculated for C₁₉ H₃₀ ClNO Theory: C, 70.45; H, 9.34; N, 4.32;Found: C, 70.52; H, 9.34; N, 4.23.

H--NMR (CDCl₃): δ0.76 (3H, d, J═7 Hz); 1.3 (3H, s); 1.72 (3H, s); 4.7(2H, d, J═5 Hz); 6.64 (1H, dd); 6.77 (1H, s); 6.86 (1H, d, J═7 Hz); 7.18(1H, t, J═6 Hz)

EXAMPLE 4trans-(±)-1-(5-Methylhexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=175°-177° C.

Analysis calculated for C₂₀ H₃₆ ClNO Theory: C, 70.66; H, 10.08; N,4.12; Found: C, 71.00; H, 9.84; N, 4.44.

H--NMR (CDCl₃): δ7.30-6.60, (m, 4H); 3.66-1.12 (m, 20H); [1.10 (d,J═7H2), 0.97 (d, J═7H2), 3H]; 0.90-0.76 (m, 5H)

EXAMPLE 5trans-(±)-1-(Cyclopentylmethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₁ ClNO Theory: C, 70.45; H, 9.34; N, 4.32;Found: C, 70.68; H, 9.14; N, 4.58.

H--NMR (CDCl₃): δ7.31-6.64 (m, 4H); 3.70-1.42 (m, 18H); [1.40 (s), 1.36(s), 3H]; [1.10 (d, J═8 Hz), 1.00 (d, J═8 Hz), 3H] ppm

EXAMPLE 6trans-(±)-1-(2-Cyclopentylethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

H--NMR (CDCl₃): δ0.76 (3H, d, J═7 Hz) 1.32 (3H, s); 2.8-2.9 (1H, m);6.65 (1H, m); 6.75 (1H, s); 6.85 (1H, d, J═8 Hz); 7.15 (1H, t, J═6 Hz)

EXAMPLE 7trans-(±)-1-[2-(2-Cyclopenten-1-yl)ethyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=100°-130° C.

Analysis calculated for C₂₀ H₃₀ ClNO Theory: C, 71.51; H, 9.00; N, 4.17;Found: C, 71.25; H, 8.92; N, 4.29.

H--NMR (CDCl₃): δ0.75 (3H, d, J═6 Hz); 1.32 (3H, s); 5.72 (2H, m); 6.65(1H, d, J═7 Hz); 6.75 (1H, s); 6.85 (1H, d, J═6 Hz); 7.16 (1H, t, J═7Hz)

EXAMPLE 8trans-(±)-1-(n-Heptyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

To a solution of 1.0 g (0.0049 mol) oftrans-(±)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine and 1.25 g (0.012mol) of triethylamine in 20 ml of N,N-dimethylformamide was added 1.8 g(0.012 mol) of heptanoyl chloride. The reaction mixture was stirred atroom temperature for approximately one hour and poured into 200 ml ofwater. The resulting mixture was extracted five times with 100 mlportions of ethyl acetate, and the organic phases were combined. Theorganic solution was washed with 200 ml of 1N hydrochloric acid, 200 mlof a saturated sodium bicarbonate solution, and 200 ml of brine, anddried over a mixture of sodium chloride and anhydrous sodium sulfate.The dried organic solution was concentrated under vacuum and the residuewas dissolved in diethyl ether. This solution was cooled toapproximately 0° C. and 600 mg (0.016 mol) of lithium aluminum hydridewas added. The mixture was stirred at room temperature for one hour and0.6 ml of water was added, followed by the addition of 1.8 ml of 15%sodium hydroxide and 0.6 ml of water. The solution was filtered and thefiltrate was dried over sodium chloride and anhydrous sodium sulfate.The organic phase was evaporated under vacuum and the residue waschromatographed over silica gel employing hexane:ethyl acetate (3:1,v:v) containing 0.5% by volume of triethylamine as the eluent. Fractionscontaining the major component were combined and the solvent wasevaporated therefrom. The hydrochloride salt was prepared to provide thetitle compound. mp=155°-157° C.

Analysis calculated for C₂₀ H₃₄ ClNO Theory: C, 70.66; H, 10.08; N,4.12; Found: C, 70.83; H, 9.79; N, 3.89.

H--NMR (CDCl₃): δ7.28-6.48 (m, 4H); 1.28 (s, 3H); 0.85 (m, 3H); 0.75 (d,3H, J═7 Hz)

Examples 9-12 were prepared by the general procedure set forth inExample 8.

EXAMPLE 9trans-(±)-1-(3-Cyclopentylpropyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=171°-174° C.

Analysis calculated for C₂₁ H₂₄ ClNO Theory: C, 71.66; H, 9.74; N, 3.98;Found: C, 71.53; H, 9.46; N, 4.06.

H--NMR (CDCl₃): δ7.19-6.48 (m, 4H); 3.60 (t, 2H, J═7 Hz); 1.25 (s, 3H);0.78 (d, 3H, J═7 Hz)

EXAMPLE 10trans-(±)-1-(Cyclohexylmethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=80° C.

Analysis calculated for C₂₀ H₃₂ ClNO Theory: C, 71.08; H, 9.55; N, 4.14;Found: C, 70.85; H, 9.48; N, 3.78.

H--NMR (CDCl₃): δ7.20-6.49 (m, 4H); 3.44 (d, 2H, J═7 Hz); 1.28 (s, 3H);0.76 (d, 3H, J═7 Hz)

EXAMPLE 11trans-(±)-1-(3-Cyclohexylpropyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=195°-197° C.

Analysis calculated for C₂₂ H₃₆ ClNO Theory: C, 72.20; H, 9.92; N, 3.83;Found: C, 71.98; H, 9.79; N, 3.85.

H--NMR (CDCl₃): δ7.19-6.48 (m, 4H); 3.60 (t, 2H, J═7 Hz); 1.28 (s, 3H);0.75 (d, 3H, J═7 Hz)

EXAMPLE 12trans-(±)-1-(3,3-Dimethylbutyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=198°-200° C.

Analysis calculated for C₁₉ H₃₂ ClNO Theory: C, 70.02; H, 9.90; N, 4.30;Found: C, 70.19; H, 9.66; N, 4.38.

H--NMR (CDCl₃): δ7.22-6.59 (m, 4H); 3.70-1.66 (m, 11H); 1.59 (s, 3H);[1.42 (s), 1.37 (s) 3H]; [1.16 (d, J═7H2), 1.02 (d, J═7H2) 3H]; 0.99 (s,3H); 0.91 (s, 3H)

EXAMPLE 13trans-(±)-1-(2-Cyclohexylethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

To a solution of 500 mg (2.4 mmol) oftrans-(±)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine dissolved in 50 mlof N,N-dimethylformamide was added 244 mg (2.9 mmol) of sodiumbicarbonate and 554 mg (2.9 mmol) of 2-cyclohexylethylbromide. Thereaction mixture was refluxed for one hour and cooled to roomtemperature. The mixture was poured into ice and the pH was adjusted toabout 9.8. The mixture was extracted with diethyl ether and the organicphases were combined and dried over anhydrous potassium carbonate. Thesolvent was evaporated under vacuum to provide 690 ml of crude material.The hydrochloride salt was prepared to provide a total of 330 mg ofcis-(±)-1-(2-cyclohexyl-ethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride. mp=178°-180° C.

Analysis calculated for C₂₁ H₃₄ ClNO Theory: C, 71.66; H, 9.74; N, 3.98;Found: C, 71.36; H, 9.93; N, 4.23.

H--NMR (CDCl₃): δ0.77 (3H, d, J═6 Hz); 1.32 (3H, s); 1.48-1.78 (10H, m);6.64 (1H, dd); 6.78 (1H, s); 6.87 (1H, d, J═6 Hz); 7.18 (1H, t, J═6 Hz)

Examples 14-16 were prepared by the general procedure outlined inExample 13.

EXAMPLE 14trans-(±)-1-(n-Pentyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₈ H₃₀ ClNO Theory: C, 69.32; H, 9.70; N, 4.49;Found: C, 69.43; H, 9.85; N, 4.67.

H--NMR (CDCl₃): δ0.75 (3H, d, J═6 Hz); 0.88 (3H, t, J═6 Hz); 1.3 (3H,s); 1.98 (1H, m); 6.64 (1H, dd); 6.75 (1H, s); 6.83 (1H, d, J═7 Hz);7.15 (1H, t, J═9 Hz)

EXAMPLE 15trans-(±)-1-(4-Methylpentyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₂ ClNO Theory: C, 70.02; H, 9.90; N, 4.30;Found: C, 69.89; H, 9.77; N, 4.27.

H--NMR (CDCl₃): δ0.77 (3H, d, J═7 Hz); 0.88 (6H, d, J═7 Hz); 1.32 (3H,s); 6.62 (1H, dd); 6.76 (1H, s); 6.83 (1H, d, J═6 Hz); 7.15 (1H, t, J═6Hz)

EXAMPLE 16trans-(±)-1-(3-Methylbutyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=155°-158° C.

Analysis calculated for C₁₈ H₃₀ ClNO Theory: C, 69.32; H, 9.70; N, 4.49;Found: C, 69.50; H, 9.66; N, 4.45.

H--NMR (CDCl₃): δ0.77 (3H, d, J═6 Hz); 0.89 (6H, d, J═6 Hz); 6.62 (1H,dd); 6.78 (1H, s); 6.87 (1H, d, J═6 Hz); 7.15 (1H, t, J═7 Hz)

EXAMPLE 17trans-(±)-1-(1-Cyclopentylpropanon-3-yl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=80°-100° C.

To a solution of 1.0 g oftrans-(±)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine in 60 ml ofN,N-dimethylformamide was added to 5.0 g of 3-cyclopentylpropen-3-one.The mixture was stirred at room temperature for 3 hours and poured intoa mixture of diethylether and water. The mixture was washed with asaturated sodium chloride solution and the organic phase was separated,dried over anhydrous potassium carbonate and concentrated under vacuumto provide 1.8 g of the free base. This material was purified over asilicone dioxide resin and converted to the hydrochloride salt toprovide the desired compound. The elemental analysis was calculated forthe free base.

Analysis calculated for C₂₁ H₃₁ NO₂ Theory: C, 76.55; H, 9.48; N, 4.25;Found: C, 76.28; H, 9.59; N, 4.12.

H--NMR (CDCl₃): δ0.74 (3H, d, J═7 Hz); 1.30 (3H, s); 6.63 (1H, d, J═8Hz); 6.74 (1H, s); 6.84 (1H, d, J═6 Hz); 7.16 (1H, t, J═6 Hz)

EXAMPLE 18trans-(±)-1-[R,S-(1-Cyclopentylpropanol-3-yl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

To a solution oftrans-(±)-1-(1-cyclopentylpropanon-3-yl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinein 100 ml of dry diethyl ether was added 2.0 ml of 1M lithium aluminumhydride in THF. The mixture was refluxed for 90 minutes and cooled toabout 0° C. Five milliliters of ethyl acetate were added to the mixturefollowed by sufficient water to result in a crystallization. The solidwas decanted and the resulting filtrate was dried over anhydrouspotassium carbonate. The filtrate was concentrated under vacuum andconverted to the hydrochloride salt to provide the desired compound. Theelemental analysis was calculated for the free base.

Analysis calculated for C₂₁ H₃₃ NO₂ Theory: C, 76.09; H, 10.03; N, 4.23;Found: C, 76.07; H, 10.09; N, 4.01.

H--NMR (CDCl₃): δ0.54 (3H, d, J═6 Hz); 1.28 (3H, s); 3.62 (1H, q, J═10Hz); 6.6 (1H, d, J═8 Hz); 6.71 (2H, t, J═9 Hz); 7.1 (1H, t, J═9 Hz);7.47 (1H, broad singlet).

Examples 19-34 were prepared by the general procedures outlined above.

EXAMPLE 19trans-(±)-1-(3-Oxo-4-methylpentyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₀ ClNO₂ Theory: C, 67.14; H, 8.90; N,4.12; Found: C, 67.43; H, 8.83; N, 3.82.

EXAMPLE 20trans-(±)-1-[R,S-(3-Hydroxy-4-methylpentyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₂ ClNO₂ Theory: C, 66.74; H, 9.43; N,4.10; Found: C, 66.54; H, 9.45; N, 4.30.

H--NMR (CDCl₃): δ0.6 (3H, t, J═6 Hz); 0.92 (3H, t, J═4 Hz); 0.98 (3H, t,J═5 Hz); 1.3 (3H, s); 6.62 (1H, d, J═8 Hz); 6.74 (2H, m); 7.12 (1H, t,J═6 Hz); 7.4-7.2 (1H, broad singlet)

EXAMPLE 21trans-(±)-1-(5-n-Hexenyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₀ ClNO Theory: C, 70.45; H, 9.34; N, 4.32;Found: C, 70.68; H, 9.13; N, 4.16.

H--NMR (CDCl₃): δ0.77 (3H, d, J═6 Hz); 1.3 (3H, s); 4.92-5.06 (2H, m);5.74-5.9 (1H, m); 6.64 (1H, m); 6.76 (1H, s); 6.85 (1H, d, J═7 Hz); 7.16(1H, t, J═7 Hz)

EXAMPLE 22trans-(±)-1-(n-Hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₂ ClNO Theory: C, 70.02; H, 9.90; N, 4.30;Found: C, 69.79; H, 10.15; N, 4.17.

H--NMR (CDCl₃): δ0.76 (3H, d, J═6 Hz); 0.82-0.92 (3H, broad triplet);1.3 (3H, s); 6.63 (1H, m); 6.75 (1H, s); 6.85 (1H, d, J═7 Hz); 7.17 (1H,t, J═7 Hz).

EXAMPLE 23trans-(+)-1-[S-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine,mp=142°-143° C.

Analysis calculated for C₂₂ H₃₅ NO₂ Theory: C, 76.48; H, 10.21; N, 4.05;Found: C, 76.64; H, 10.48; N, 4.17.

EXAMPLE 24trans-(-)-1-[S-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine,mp=151°-152° C.

[α]₅₈₉ =-64.9655, [α]₃₆₅ =-211.655

Analysis calculated for C₂₂ H₃₅ NO₂ Theory: C, 76.48; H, 10.21; N, 4.05;Found: C, 76.71; H, 10.43; N, 4.05.

EXAMPLE 25trans-(+)-1-[R-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine,mp=150°-151° C.

[α]₅₈₉ =+73.6069, [α]₃₆₅ =+238.963

Analysis calculated for C₂₂ H₃₅ NO₂ Theory: C, 76.48; H, 10.21; N, 4.05;Found: C, 76.24; H, 9.92; N, 4.18.

EXAMPLE 26trans-(-)-1-[R-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine,mp=141°-143° C.

[α]₅₈₉ =-68.81, [α]₃₆₅ =-223.88,

Analysis calculated for C₂₂ H₃₅ NO₂ Theory: C, 76.48; H, 10.21; N, 4.05;Found: C, 76.40; H, 10.35; N, 4.01.

EXAMPLE 27trans-(±)-1-[R,S-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₂₂ H₃₆ ClNO₂ Theory: C, 69.18; H, 9.50; N,3.67; Found: C, 68.97; H, 9.37; N, 3.70.

EXAMPLE 28trans-(+)-1-(5-Methylhexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride [α]₃₆₅ =+195.429

Analysis calculated for C₂₀ H₃₄ ClNO Theory: C, 70.66; H, 10.08; N,4.12; Found: C, 70.42; H, 9.95; N, 4.09.

EXAMPLE 29trans-(-)-1-(5-Methylhexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride [α]₃₆₅ =-207.669

Analysis calculated for C₂₀ H₃₄ ClNO Theory: C, 70.66; H, 10.08; N,4.12; Found: C, 70.40; H, 10.31; N, 4.32.

EXAMPLE 30trans-(±)-1-[R,S-(3-Hydroxyhexyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₂ ClNO₂ Theory: C, 66.74; H, 9.43; N,4.10; Found: C, 66.90; H, 9.20; N, 4.19.

EXAMPLE 31trans-(±)-1-[R,S-(3-Methoxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=171°-173° C.

Analysis calculated for C₂₃ H₃₈ ClNO₂ Theory: C, 69.76; H, 9.67; N,3.54; Found: C, 70.00; H, 9.93; N, 3.45.

EXAMPLE 32trans-(±)-1-(3-Oxo-n-octyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=122°-123° C.

Analysis calculated for C₂₁ H₃₄ ClNO₂ Theory: C, 68.55; H, 9.31; N,3.81; Found: C, 68.82; H, 9.51; N, 3.71.

EXAMPLE 33trans-(±)-1-(3-Oxo-3-cyclohexylpropyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=170°-173° C.

Analysis calculated for C₂₂ H₃₅ ClNO₂ Theory: C, 69.54; H, 9.02; N,3.69; Found: C, 69.39; H, 8.84; N, 3.85.

EXAMPLE 34trans-(±)-1-(3-Oxo-n-hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₁₉ H₃₀ ClNO₂ Theory: C, 69.14; H, 8.96; N,4.12; Found: C, 69.36; H, 8.85; N, 4.34.

EXAMPLE 35trans-(±)-1-[3-(2-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

A. 3-(2-Thienyl)propionyl chloride

To a solution of 5.0 g (0.032 mol) of 3-(2-thienyl)propionic acid in 2ml of methylene chloride and 25 ml of oxalyl chloride was added threedrops of N,N-dimethylformamide slowly. Following evolution of the gasthe reaction mixture was concentrated under vacuum and 20 ml of hexanewas added to the residue. The resulting mixture was filtered and thefiltrate was concentrated under vacuum. The resulting compound,3-(2-thienyl)propionyl chloride, was used directly in the followingreaction.

B. To a solution of 1.0 g (4.9 mmol) oftrans-(±)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine and 2.6 g of1,8-bis(dimethylamino)naphthalene dissolved in 30 ml ofN,N-dimethylformamide was added a solution of 2.2 g (0.0126 mol) of3-(2-thienyl)propionyl chloride dissolved in 20 ml ofN,N-dimethylformamide dropwise. The reaction mixture was stirred at roomtemperature for approximately one hour and poured into 250 ml of water.The mixture was extracted with five 100 ml portions of ethyl acetate.The organic extracts were combined, washed with 1N hydrochloric acid, anaqueous saturated sodium bicarbonate solution, and a saturated sodiumchloride solution and dried over a mixture of sodium chloride andanhydrous sodium sulfate. The organic phase was evaporated under vacuumand the residue was dissolved in 200 ml of toluene. This mixture wasevaporated and the residue was dissolved in 50 ml of tetrahydrofuran.The mixture was cooled to about 0° C., a solution of 5 ml of Red-Al(3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluenefrom Aldrich Chemical Company, Milwaukee, Wis.) in 50 ml oftetrahydrofuran was added. The resulting mixture was stirred at roomtemperature for approximately one hour and 100 ml of pH 10 buffer wasadded. This solution was extracted with two 100 ml portions of ethylacetate. The organic extracts were combined, washed with an aqueoussaturated sodium chloride solution and dried over sodium chloride andanhydrous sodium sulfate. The organic solution was evaporated undervacuum and the residue was dissolved in 50 ml of ethyl acetate. Themixture was extracted with two 100 ml portions of 1N hydrochloric acidand the acidic extracts were combined and washed with diethyl ether. ThepH of the aqueous mixture was adjusted to about 9.8 with sodiumhydroxide, and the aqueous mixture was extracted twice with a total of200 ml ethyl acetate. The extracts were combined and washed with anaqueous saturated sodium chloride solution, dried over sodium chlorideand anhydrous sodium sulfate and concentrated under vacuum. Theresulting residue was chromatographed employing hexane:ethyl acetate(3:1, v:v) containing 0.5% triethylamine by volume as the eluant. Thehydrochloride salt was prepared to provide the title compound.mp=101°-103° C.

Analysis calculated for C₂₀ H₂₈ ClNOS Theory: C, 65.64; H, 7.71; N,3.83; Found: C, 65.37; H, 7.98; N, 4.02.

H--NMR (CDCl₃): δ7.21-6.50 (m, 7H); 1.27 (s, 3H); 0.77 (d, 3H, J═7 Hz)

Following the general procedures set forth above the remaining Exampleswere prepared.

EXAMPLE 36trans-(+)-1-[3-(2-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine,mp=110°-112° C.

Analysis calculated for C₂₀ H₂₈ ClNOS Theory: C, 65.64; H, 7.71; N,3.83; Found: C, 65.40; H, 7.49; N, 3.77.

H--NMR (CDCl₃): δ7.4-6.54 (m, 7H); 3.46-1.7 (m, 13H); 1.34 (s, 3H); 0.76(d, 3H, J═7 Hz)

EXAMPLE 37trans-(-)-1-[3-(2-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

M⁺ =329

Analysis calculated for C₂₀ H₂₈ ClNOS Theory: C, 65.64; H, 7.71; N,3.83; Found: C, 65.94; H, 7.49; N, 3.95.

H--NMR (CDCl₃): δ7.4-6.54 (m, 7H); 3.46-1.7 (m, 13H); 1.34 (s, 3H); 0.76(d, 3H, J═7 Hz)

EXAMPLE 38trans-(±)-1-[2-(2-Thienyl)ethyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=117°-119° C.

Analysis calculated for C₁₉ H₂₆ ClNOS Theory: C, 64.84; H, 7.45; N,3.98; Found: C, 65.09; H, 7.62; N, 3.69.

EXAMPLE 39trans-(±)-1-[3-Oxo-3-(2-thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=118°-120° C.

Analysis calculated for C₂₀ H₂₆ ClNO₂ S Theory: C, 63.22; H, 6.70; N,3.67; Found: C, 62.78; H, 6.31; N, 3.68.

EXAMPLE 40trans-(±)-1-[R,S-[3-Hydroxy-3-(2-thienyl)-propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride, mp=97°-99° C.

Analysis calculated for C₂₀ H₂₈ ClNO₂ S Theory: C, 62.89; H, 7.39; N,3.67; Found: C, 62.79; H, 7.36; N, 3.73.

EXAMPLE 41trans-(±)-1-[3-(3-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinehydrochloride

Analysis calculated for C₂₀ H₂₈ ClNOS Theory: C, 65.64; H, 7.71; N,3.83; Found: C, 65.42; H, 7.52; N, 3.92.

As noted above, the compounds of the present invention are useful inblocking the effect of agonists at mu or kappa receptors. As such, thepresent invention also provides a method for blocking mu or kappareceptors in mammals comprising administering to a mammal requiringblocking of a mu or kappa receptor a receptor blocking dose of acompound of the invention.

The term "receptor blocking dose", as defined herein, means an amount ofcompound necessary to block a mu or kappa receptor followingadministration to a mammal requiring blocking of a mu or kappa receptor.The active compounds are effective over a wide dosage range. Forexample, dosages per day will normally fall within the range of about0.05 to about 250 mg/kg of body weight. In the treatment of adulthumans, the range of about 0.5 to about 100 mg/kg, in single or divideddoses, is preferred. However, it will be understood that the amount ofthe compound actually administered will be determined by a physician inlight of the relevant circumstances, including the condition to betreated, the choice of compound to be administered, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the chosen route of administration, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. The compounds may be administered by a variety of routessuch as the oral, transdermal, subcutaneous, intranasal, intramuscularand intravenous routes.

A variety of physiologic functions have been shown to be subject toinfluence by mu and kappa receptors in the brain. As such, the compoundsof the present invention are believed to have the ability to treat avariety of disorders in mammals associated with these receptors such aseating disorders, opiate overdose, depression, smoking, alcoholismsexual dysfunction, shock, stroke, spinal damage and head trauma. Assuch, the present invention also provides methods of treating the abovedisorders at rates set forth above for blocking the effect of agonistsat mu or kappa receptors.

The compounds of the present invention have been found to displayexcellent activity in an opioid receptor binding assay which measuresthe ability of the compounds to block the mu or kappa receptors. Thisassay was conducted by the following procedure.

Male Sprague Dawley rats for mu and delta site experiments and maleHartley guinea pigs for kappa site experiments were sacrificed viadecapitation and the brains were removed. The brain tissue, rat wholebrain minus cerebellum for mu and delta sites and guinea pig cortex forthe kappa site, was homogenized in a Teflon and glass tissuehomogenizer. A supernatant I, pellet IV, fraction was frozen in anitrogen freezer at 1.33 g/ml concentration and stored for not longerthan five weeks prior to use. Pellets were rehydrated with physiologicalbuffer prior to use.

For mu and delta sites increasing concentrations of experimentalcompound, (0.1 to 1000 nanomolar (nM)), Kreb-Hepes buffer pH 7.4, and ³H ligand were combined in polystyrene tubes at room temperature. Thereaction was initiated by the addition of the rehydrated tissue whichhas been preincubated at 37° C. for 20 minutes. The reaction mixture wasincubated in a 37° C. water bath for 20 minutes. The reaction wasterminated by rapid filtration, (Amicon vacuum manifolds), throughWhatman GF/C glass filters that had been presoaked in Krebs-Hepes bufferpH 7.4. The filters were then washed 2× with 5 ml of ice coldKrebs-Hepes buffer pH 7.4. Washed filters were placed in scintillationvials and 10 ml PCS, (Amersham), was added and samples counted in aSearle D-300 beta counter. Means and standard error statistics werecalculated for triplicate experimental determinations in certain cases.The procedure was slightly modified for the kappa site. The tissue waspretreated with 100 nM concentrations of mu and delta receptor siteblockers. The incubation time for the reaction mixture was 45 minutes at37° C.

Ki values were calculated using a minitab statistical program accordingto the following formula: ##EQU1## wherein IC₅₀ is the concentration atwhich 50% of the ³ H ligand is displaced by the test compound and K_(D)is the dissociation constant for the ³ H ligand at the receptor site.

The results of the evaluation of certain compounds of the presentinvention in the opioid receptor binding assay are set forth below inTable I. In the Table, column 1 sets forth the Example Number of thecompound evaluated; column 2, the Ki value in nanomolar (nM) at the mureceptor; and column 3, the Ki value in nM at the kappa receptor. Alsoin the Table, compounds identified as Compounds A-F in Tables I-IV whichfollow are known compounds which were evaluated to compare theiractivity to the compounds of the present invention. Compounds A-F havethe following identities:

Compound A:4β-(3-Hydroxyphenyl)-3β,4α-dimethyl-α-phenyl-1-piperidinepropanolhydrochloride

Compound B: 3-(1,3α,4β-Trimethyl-4α-piperidyl)phenol hydrochloride

Compound C:3-[4β-(3-Hydroxyphenyl)-3β,4α-dimethylpiperidino]propiophenone maleate

Compound D: 3-(3α,4β-Dimethyl-1-phenethyl-4α-piperidyl)phenolhydrochloride

Compound E: naloxone

Compound F: naltrexone

                  TABLE I                                                         ______________________________________                                        Opioid Receptor Binding Displacement Assay                                    Example No.                                                                   of Compound   Ki        Ki                                                    Tested        Mu (nM)   Kappa (nM)                                            ______________________________________                                         1            1.10      5.20                                                   2            5.61      5.79                                                   3            2.95 ± 1.12                                                                          13.89 ± 6.66                                        4            0.46 ± 0.20                                                                          6.04 ± 0.44                                         6            0.94      7.18                                                   7            12.06     1.04                                                   8            0.62      --                                                     9            0.37 ± 0.07                                                                          3.41 ± 0.08                                        10            17.10     28.2                                                  11            0.49      2.34                                                  13            0.65 ± 0.12                                                                          2.32 ± 0.26                                        14            4.33      --                                                    15            1.25 ± 0.40                                                                          9.43 ± 1.67                                        16            31.75     70.10                                                 17            0.84      0.55                                                  18            0.41      5.47                                                  21            1.61      --                                                    22            0.29      9.62                                                  23            0.41 ± 0.09                                                                          2.02 ± 0.46                                        24            1.40 ± 0.61                                                                          11.45 ± 4.29                                       25            2.40 ± 0.61                                                                          11.45 ± 4.29                                       26            2.24 ± 0.17                                                                          14.29 ± 2.10                                       27            0.22 ± 0.03                                                                          5.04 ±  0.58                                       28            0.89      1.91                                                  29            1.36      3.04                                                  31            0.77      3.82                                                  35            0.56      6.10                                                  36            0.20 ± 0.08                                                                          3.29 ± 1.02                                        37            1.78 ± 0.10                                                                          12.47 ± 1.34                                       38            5.28      --                                                    40            0.50      11.70                                                 41            --        10.30                                                 Compound A    1.0       22.7                                                  Compound B    80.0      833.0                                                 Compound C    5.4       208.0                                                 Compound D    1.2       51.0                                                  Compound E    6.3       66.4                                                  Compound F    0.8       3.8                                                   ______________________________________                                    

The compounds of the invention also demonstrate excellent activity in anin vivo mu and kappa opioid receptor antagonist test in mice. Theprocedure used to establish this activity follows.

In order to determine in vivo opioid receptor antagonism, the writhingtest, usually used for measuring analgesia, was used with mice. Themouse writhing response was defined as a contraction of the abdominalmusculature, followed by the extension of the hind limbs. Writhing wasinduced by the intraperitoneal administration of 0.6% acetic acid in avolume of 1 ml/100 g of body weight. Five CF-1 male mice (Charles River,Portage, Mich.), weighing approximately 20-22 grams each after beingfasted overnight, were observed simultaneously for 10 minutes for thewrithing response, beginning five minutes after injection of aceticacid. The percent inhibition of writhing was calculated from the averagenumber of writhes in the control group. Each dose combination wasadministered to five mice.

Each potential opioid antagonist was administered in various doses withan analgesic dose of morphine, a prototypical mu opioid receptoragonist, and an analgesic dose of U-50,488H, a prototypical kappa opioidreceptor agonist. The respective doses were 1.25 and 2.5 mg/kg s.c.These doses produce between 90 and 100% inhibition of writhing. Eachpotential antagonist was tested at 1.25 mg/kg s.c. with morphine andU-50,488. If there was a significant antagonism of the analgesia ofeither morphine or U-50,488, then enough subsequent doses of theantagonist would be tested so as to generate a complete dose-responsecurve and to calculate an antagonist dose-50 (AD₅₀). The AD₅₀ wascalculated from a linear regression equation of probit-plotted data anddefines the estimated dose which reduces the analgesic effect of theagonist to 50% inhibition of writhing. Injections of test drugs and theprototypical agonists occurred 20 minutes before the injection of aceticacid.

The results of the foregoing mouse writhing assay are set forth below inTable II. In the Table, column 1 provides the Example Number of thecompound evaluated in the assay; column 2, the amount of the compoundevaluated in mg/kg necessary to reduce the analgesic effect of theagonist at the mu receptor to 50% inhibition of writhing; and column 3,the amount of the compound evaluated in mg/kg necessary to reduce theanalgesic effect of the agonist at the kappa receptor to 50% inhibitionof writhing.

                  TABLE II                                                        ______________________________________                                        Mouse Writhing Assay                                                          Example No.                                                                   of Compound  Mu          Kappa                                                Tested       AD.sub.50 (mg/kg)                                                                         AD.sub.50 (mg/kg)                                    ______________________________________                                         1           0.26        0.22                                                  2           0.21        0.29                                                  3           0.08        0.29                                                  4           0.35        0.23                                                  5           1.01        0.54                                                  6           0.13        0.22                                                  7           0.11        0.12                                                  8           0.21        0.64                                                  9           0.12        0.13                                                 10           0.46        0.34                                                 11           0.19        0.35                                                 12           0.56        0.42                                                 13           0.10        0.12                                                 14           0.37        0.60                                                 15           0.11        0.09                                                 16           0.87        0.62                                                 17           0.21        0.19                                                 18           0.04        0.08                                                 20           0.14        0.35                                                 22           0.05        0.11                                                 23           0.01        0.07                                                 24           0.05        0.24                                                 25           0.03        0.36                                                 26           0.07        0.52                                                 27           0.07        0.14                                                 28           0.08        0.22                                                 29           0.35        0.89                                                 30           0.11        0.47                                                 31           1.42        0.44                                                 32           0.17        3.50                                                 33           0.12        0.26                                                 35           0.22        0.30                                                 36           0.05        0.11                                                 37           0.24        0.65                                                 38           0.25        0.25                                                 40            0.065      0.14                                                 41           0.12        0.24                                                 Compound A   0.05        0.92                                                 Compound B   0.74        2.50                                                 Compound C   0.14        4.5                                                  Compound D   0.16        1.38                                                 Compound E   0.08        1.12                                                 Compound F   0.05        0.06                                                 ______________________________________                                    

It is well documented that marked diuretic effects are derived from theinteraction of opioid antagonists with the kappa-opioid receptor ofmammals See, e.g., Leander The Journal of Pharmacology and ExperimentalTherapeutics Vol. 224, No. 1, 89-94 (1983). As such, the compounds ofthe invention were also evaluated in a rat diuresis assay conductedaccording to the following procedure described by Leander et al. in DrugDevelopment Research 4:421-427 (1984) in an effort to further establishthe ability of the present compounds to block kappa receptors.

According to this procedure, sixty male Long-Evans hooded rats (CharlesRiver Breeding Laboratories, Portage, Mich.) weighing between about 300and 500 grams each were housed either individually or in pairs in atemperature-controlled (23° C.) colony room which was illuminatedbetween 6:00 A.M. and 6:00 P.M. Rodent chow and tap water werecontinuously available except during the measurement of urine output.The animals were used repeatedly, but no more frequently than twice aweek.

In determining the antagonist activity of the present compounds, eachanimal was injected with 0.8 mg/kg of bremazocine, a potent kappaagonist, to induce urination. The animals were then injected withvarious doses of the test compounds. To measure urine output, theanimals were removed from the home cages, weighed, injected and placedin metabolism cages for 5 hr. Excreted urine was funneled into graduatedcylinders. Cumulative urine volumes were determined at designated timeintervals, usually at 2 and 5 hr after injection.

The compounds which are salt forms were dissolved in distilled water. Ifnecessary, the compounds were dissolved in distilled water with the aidof either a few drops of lactic acid or hydrochloric acid and gentlewarming. All injections were s.c. in a volume of 1 ml/kg of body weight.During tests for antagonism, two injections were given, one on each sideof the body.

The results of the rat diuresis study are set forth below in Table III.In the Table, column 1 provides the Example Number of the compoundtested; column 2, the amount of compound in mg/kg necessary to reducethe urinary output to 50% of the effect produced by 0.08 mg/kg ofbremazocine alone two hours after injection of bremazocine and the testcompound; and column 3, the amount of compound in mg/kg necessary toreduce the urinary output to 50% of the effect produced by 0.08 mg/kg ofbremazocine alone five hours after injection of bremazocine and the testcompound.

                  TABLE III                                                       ______________________________________                                        Rat Diuresis Assay                                                                            AD.sub.50 (mg/kg)                                             Example No. of    Two     Five                                                Compound Tested   Hours   Hours                                               ______________________________________                                         3                0.27    0.39                                                 4                0.17    0.46                                                 5                1.91    0.92                                                 6                --      0.67                                                 7                1.30    1.38                                                 8                3.77    3.33                                                 9                2.40    0.79                                                10                14.90   3.90                                                11                1.90    1.02                                                12                7.89    8.13                                                14                0.78    0.69                                                15                0.27    0.39                                                16                7.70    4.45                                                22                1.31    0.70                                                23                0.40    0.38                                                35                2.20    1.04                                                36                4.65    1.65                                                37                2.92    1.66                                                38                --      2.00                                                40                3.78    1.44                                                41                2.70    1.90                                                Compound A        4.09    2.65                                                Compound E        2.71    3.49                                                Compound F        2.17    2.45                                                ______________________________________                                    

The compounds of the present invention have also been found to have theability to decrease the amount of food consumed in vivo. The followingassay was employed to evaluate the ability of the compounds of theinvention to effect food and water consumption of meal fed obese Zuckerrats.

According to this procedure, 3-4 month old obese Zucker rats weretrained to eat food daily from 8:00 A.M. to 4:00 P.M. only, such thatthe body weight gain approximates that if the rats were fed ad libitum.These rats were allowed to consume water at all times. Four groups ofrats with four rats in each group, two female and two male, were formed.One group served as control for the other three groups each day. Each ofthe other groups were given a subcutaneous dose of the compound to beevaluated. The test compound was formulated in physiological salinecontaining 10% dimethylsulfoxide by volume.

Animals remained drug free for 4 days before the next test. Food andwater consumption of each rat were measured for the first four hours. Atest on one compound was run for three consecutive days. The drug effectwas expressed as the percent of the control for that test day.

The results of this test are set forth below in Table IV. In the Table,column 1 gives the Example Number of the compound evaluated; and column2 provides the ED₂₀ in mg/kg, wherein ED₂₀ represents the amount ofcompound evaluated in mg/kg necessary to decrease food consumption 20%during the first four hours of the experiment.

                  TABLE IV                                                        ______________________________________                                        Food Consumption Assay                                                        Example No. of   ED.sub.20                                                    Compound Tested  (mg/kg)                                                      ______________________________________                                         1               0.08                                                          2               1.25                                                          3               0.29                                                          4               0.05                                                          6               0.33                                                          7               0.34                                                          8               0.44                                                          9               1.25                                                         10               1.25                                                         11               0.15                                                         13               4.56                                                         14               4.47                                                         15               3.65                                                         16               >20.0                                                        17               0.31                                                         18               0.07                                                         20               0.91                                                         21               9.37                                                         22               0.78                                                         23               0.05                                                         24               0.12                                                         25               0.13                                                         26               0.35                                                         27               0.04                                                         28               0.12                                                         29               0.31                                                         35               0.08                                                         36               0.05                                                         37               0.19                                                         40               0.11                                                         Compound A       0.55                                                         Compound B       3.99                                                         Compound C       3.72                                                         Compound D       0.94                                                         Compound E       1.40                                                         Compound F       2.05                                                         ______________________________________                                    

While it is possible to administer a compound of the invention directlywithout any formulation, the compounds are preferably employed in theform of a pharmaceutical formulation comprising a pharmaceuticallyacceptable carrier, diluent or excipient and a compound of theinvention. Such compositions will contain from about 0.1 percent byweight to about 90.0 percent by weight of a present compound. As such,the present invention also provides pharmaceutical formulationscomprising a compound of the invention and a pharmaceutically acceptablecarrier, diluent or excipient therefor.

In making the compositions of the present invention, the activeingredient will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions,aerosols (as a solid or in a liquid medium), and soft and hard gelatincapsules.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate,water, and mineral oil. The formulations may also include wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

For oral administration, a compound of this invention ideally can beadmixed with carriers and diluents and molded into tablets or enclosedin gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, more usually about 5 toabout 300 mg, of the active ingredient. The term "unit dosage form"refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as active compounds any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                        Amount Concentration                                                          Per    by Weight                                                              Capsule                                                                              (percent)                                              ______________________________________                                        trans-(+)-1-[S-(3-hydroxy-3-                                                                    250    mg    55.0                                           cyclohexylpropyl)]-3,4-                                                       dimethyl-4-(3-hydroxy-                                                        phenyl)piperidine                                                             hydrochloride                                                                 starch dried      200    mg    43.0                                           magnesium stearate                                                                              10     mg     2.0                                                             460    mg    100.0                                          ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

    ______________________________________                                                          Amount Concentration                                                          Per    by Weight                                                              Capsule                                                                              (percent)                                            ______________________________________                                        trans-(±)-1-[R-(3-hydroxy-3-cyclo-                                                             20     mg    10.0                                         hexylpropyl)]-3,4-dimethyl-4-                                                 (3-hydroxyphenyl)piperidine                                                   starch              89     mg    44.5                                         microcrystalline    89     mg    44.5                                         cellulose                                                                     magnesium stearate  2      mg     1.0                                                             200    mg    100.0                                        ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of active ingredient are made asfollows:

    ______________________________________                                                       Amount   Concentration                                                        Per      by Weight                                                            Capsule  (percent)                                             ______________________________________                                        trans-(±)-1-(3-oxo- -n-octyl)-                                                              100     mg     30.0                                          3,4-dimethyl-4-(3-hydroxy-                                                    phenyl)piperidine                                                             hydroiodide                                                                   polyoxyethylene sorbitan                                                                       50      mcg     0.02                                         monooleate                                                                    starch powder    250     mg     69.98                                                          350.05  mg     100.00                                        ______________________________________                                    

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets each containing 10 mg of active ingredient are prepared asfollows:

    ______________________________________                                                        Amount Concentration                                                          Per    by Weight                                                              Capsule                                                                              (percent)                                              ______________________________________                                        trans-(±)-1-(5-methylhexyl)-                                                                 10     mg    10.0                                           3,4-dimethyl-4-(3-hydroxy-                                                    phenyl)piperidine maleate                                                     starch            45     mg    45.0                                           microcrystalline  35     mg    35.0                                           cellulose                                                                     polyvinylpyrrolidone                                                                            4      mg    4.0                                            (as 10% solution                                                              in water)                                                                     sodium carboxymethyl                                                                            4.5    mg    4.5                                            starch                                                                        magnesium stearate                                                                              0.5    mg    0.5                                            talc              1      mg    1.0                                                              100    mg    100.0                                          ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formula may be prepared using the ingredients below:

    ______________________________________                                                          Amount Concentration                                                          Per    by Weight                                                              Capsule                                                                              (percent)                                            ______________________________________                                        trans-(±)-1-[S-(3-hydroxy-3-cyclo-                                                             250    mg    38.0                                         hexylpropyl)]-3,4-dimethyl-4-                                                 (3-hydroxyphenyl)piperidine                                                   hydrochloride                                                                 cellulose           400    mg    60.0                                         microcrystalline                                                              silicon dioxide fumed                                                                             10     mg     1.5                                         stearic acid        5      mg     0.5                                                             665    mg    100.0                                        ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are made asfollows:

    ______________________________________                                                               per 5 ml of                                                                   suspension                                             ______________________________________                                        trans-(±)-1-(3-hydroxy- -n-hexyl)-3,4-                                                              5 mg                                                 dimethyl-4-(3-hydroxyphenyl)-                                                 piperidine hydrochloride                                                      sodium carboxymethyl cellulose                                                                         50 mg                                                syrup                    1.25 ml                                              benzoic acid solution    0.10 ml                                              flavor                   q.v.                                                 color                    q.v.                                                 water                    q.s. to 5 ml                                         ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

    ______________________________________                                                           Concentration by                                                              Weight (percent)                                           ______________________________________                                        trans-(±)-1-[R-(3-methoxy-3-cyclo-                                                               0.25                                                    hexylpropyl)]-3,4-dimethyl-4-                                                 (3-hydroxyphenyl)piperidine                                                   hydrochloride                                                                 ethanol              29.75                                                    Propellant 22        70.00                                                    (chlorodifluoromethane)                                                                            100.00                                                   ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

We claim:
 1. A method of treating a disorder selected from the groupconsisting of spinal damage, stroke and head trauma in humans comprisingadministering to a human in need of such treatment an effective dose ofa trans-3,4 isomer of a compound of the formula ##STR19## wherein: R¹ ishydrogen or C₁ -C₄ alkanoyl;R² is hydrogen, C₁ -C₄ alkyl or C₂ -C₆alkenyl; R³ is C₄ -C₈ cycloalkyl, C₄ -C₈ cycloalkenyl, C₁ -C₆ alkyl, C₂-C₆ alkenyl, C₁ -C₄ alkyl substituted C₄ -C₈ cycloalkyl, C₁ -C₄ alkylsubstituted C₄ -C₈ cycloalkenyl or thiophene; Z is ##STR20## or a bond;R⁴ is hydrogen, C₁ -C₆ alkyl, ##STR21## or ##STR22## R⁵ is C₁ -C₄ alkylor ##STR23## n is 1, 2 or 3; or a pharmaceutically acceptable saltthereof.
 2. The method of claim 1 wherein said disorder is shock.
 3. Amethod of claim 2 wherein R³ is C₄ -C₈ cycloalkyl.
 4. A method of claim3 wherein R³ is cyclohexyl.
 5. The method of claim 4 which is the(+)-trans isomer
 6. The method of claim 5 which istrans-(+)-1-[S-(3-hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine.7. The method of claim 1 wherein said disorder is spinal damage.
 8. Amethod of claim 7 wherein R³ is C₄ -C₈ cycloalkyl.
 9. A method of claim8 wherein R³ is cyclohexyl.
 10. The method of claim 9 which is the(+)-trans isomer
 11. The method of claim 10 which istrans-(+)-1-[S-(3-hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine.12. The method of claim 1 wherein said disorder is stroke.
 13. A methodof claim 12 wherein R³ is C₄ -C₈ cycloalkyl.
 14. A method of claim 13wherein R³ is cyclohexyl.
 15. The method of claim 14 which is the(+)-trans isomer.
 16. The method of claim 15 which istrans-(+)-1-[S-(3-hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine.17. The method of claim 1 wherein said disorder is head trauma.
 18. Amethod of claim 17 wherein R³ is C₄ -C₈ cycloalkyl.
 19. A method ofclaim 18 wherein R³ is cyclohexyl.
 20. The method of claim 19 which isthe (+)-trans isomer.
 21. The method of claim 20 which istrans-(+)-1-[S-(3-hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine.22. A pharmaceutical formulation comprising an effective amount of atrans-3,4 isomer of a compound of the formula ##STR24## wherein: R¹ ishydrogen or C₁ -C₄ alkanoyl;R² is hydrogen, C₁ -C₄ alkyl or C₂ -C₆alkenyl; R³ is C₄ -C₈ cycloalkyl, C₄ -C₈ cycloalkenyl, C₁ -C₆ alkyl, C₂-C₆ alkenyl, C₁ -C₄ alkyl substituted C₄ -C₈ cycloalkyl, C₁ -C₄ alkylsubstituted C₄ -C₈ cycloalkenyl or thiophene; Z is ##STR25## or a bond;R⁴ is hydrogen, C₁ -C₆ alkyl, ##STR26## or ##STR27## R⁵ is C₁ -C₄ alkylor ##STR28## n is 1, 2 or 3; or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier, diluted or excipienttherefor.
 23. A pharmaceutical formulation of claim 22 wherein R³ is C₄-C₈ cycloalkyl.
 24. A pharmaceutical formulation of claim 23 wherein R³is cyclohexyl.
 25. The pharmaceutical formulation of claim 24 which isthe (+)-trans isomer
 26. The pharmaceutical formulation of claim 25which istrans-(+)-1-[S-(3-hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine.